Daniel Munblit

Factors affecting breast milk composition and potential consequences for development of the allergic phenotype

There is conflicting evidence on the protective role of breastfeeding in relation to allergic sensitization and disease. The factors in breast milk which influence these processes are still unclear and under investigation. We know that colostrum and breast milk contain a variety of molecules which can influence immune responses in the gut‐associated lymphoid tissue of a neonate. This review summarizes the evidence that variations in colostrum and breast milk composition can influence allergic outcomes in the infant, and the evidence that maternal and environmental factors can modify milk composition. Taken together, the data presented support the possibility that maternal dietary interventions may be an effective way to promote infant health through modification of breast milk composition.

Human Milk and Allergic Diseases: An Unsolved Puzzle.

There is conflicting evidence on the protective role of breastfeeding in relation to the development of allergic sensitisation and allergic disease. Studies vary in methodology and definition of outcomes, which lead to considerable heterogeneity. Human milk composition varies both within and between individuals, which may partially explain conflicting data. It is known that human milk composition is very complex and contains variable levels of immune active molecules, oligosaccharides, metabolites, vitamins and other nutrients and microbial content. Existing evidence suggests that modulation of human breast milk composition has potential for preventing allergic diseases in early life. In this review, we discuss associations between breastfeeding/human milk composition and allergy development.

Allergy prevention by breastfeeding: possible mechanisms and evidence from human cohorts.

Purpose of reviewAllergy is a modern disease which does not seem to benefit from breast milk preventive effects. We propose that maternal milk composition has not adapted to the needs of allergy prevention because of the recent and rapid increase of allergy. Modulation of breast milk composition may be the best strategy to counteract allergy development. We will review recent advances in understanding of allergy physiopathology and how breast milk factors may be specifically appropriate to interfere with allergy development in early life. Recent findingsThere is strong evidence both from rodent and human studies that breast milk factors may impact on parameters which are now recognized to be essential for allergy physiopathology: infant gut barrier function, microbiota metabolites production, and oral tolerance induction. Data from human cohorts support the possibility to modify breast milk composition by selected interventions and to impact health outcomes in offspring. SummaryNutritional intervention in lactating mothers should endow breast milk with the capacity to combat allergy epidemics in addition to infectious disease.

Immune components in human milk are associated with early infant immunological health outcomes: A prospective three-country analysis

The role of breastfeeding in improving allergy outcomes in early childhood is still unclear. Evidence suggests that immune mediators in human milk (HM) play a critical role in infant immune maturation as well as protection against atopy/allergy development. We investigated relationships between levels of immune mediators in colostrum and mature milk and infant outcomes in the first year of life. In a large prospective study of 398 pregnant/lactating women in the United Kingdom, Russia and Italy, colostrum and mature human milk (HM) samples were analysed for immune active molecules. Statistical analyses used models adjusting for the site of collection, colostrum collection time, parity and maternal atopic status. Preliminary univariate analysis showed detectable interleukin (IL) 2 and IL13 in HM to be associated with less eczema. This finding was further confirmed in multivariate analysis, with detectable HM IL13 showing protective effect OR 0.18 (95% CI 0.04–0.92). In contrast, a higher risk of eczema was associated with higher HM concentrations of transforming growth factor β (TGFβ) 2 OR 1.04 (95% CI 1.01–1.06) per ng/mL. Parental-reported food allergy was reported less often when IL13 was detectable in colostrum OR 0.10 (95% CI 0.01–0.83). HM hepatocyte growth factor (HGF) was protective for common cold incidence at 12 months OR 0.19 (95% CI 0.04–0.92) per ng/mL. Data from this study suggests that differences in the individual immune composition of HM may have an influence on early life infant health outcomes. Increased TGFβ2 levels in HM are associated with a higher incidence of reported eczema, with detectable IL13 in colostrum showing protective effects for food allergy and sensitization. HGF shows some protective effect on common cold incidence at one year of age. Future studies should be focused on maternal genotype, human milk microbiome and diet influence on human milk immune composition and both short- and long-term health outcomes in the infant.

Breast-Milk Characteristics Protecting Against Allergy

Breast milk and colostrum are the first feeding sources for a child, providing nutrients, growth factors and immunological components, which are crucial for the newborns correct development and health. Length of exclusive breastfeeding and time of solid foods introduction is a key factor that may influence allergy development. There is an emerging evidence of a relationship between breastfeeding, milk composition and lower risk of chronic diseases, such as diabetes, obesity, hypertension and allergies. This review examines current evidence regarding humoral and cellular characteristics of breast-milk, and potential role of environment, maternal diet and breastfeeding on the allergy development in children.

Colostrum and Mature Human Milk of Women from London, Moscow, and Verona: Determinants of Immune Composition

Cytokines and growth factors in colostrum and mature milk may play an important role in infant immune maturation, and may vary significantly between populations. We aimed to examine associations between environmental and maternal factors, and human milk (HM) cytokine and growth factor levels. We recruited 398 pregnant/lactating women in the United Kingdom, Russia, and Italy. Participants underwent skin prick testing, questionnaire interview, and colostrum and mature milk sampling. HM cytokine and growth factor levels were quantified by electro-chemiluminescence. We found significant geographical variation in growth factor levels, but no evidence of variation between sites in cytokine detectability. There was an inverse correlation between time of milk sampling and growth factor levels in colostrum for Hepatocyte Growth Factor (HGF) and TGFβ1 and TGFβ3, but not TGFβ2, and levels were significantly higher in colostrum than mature milk for all growth factors. The kinetics of decline were different for each growth factor. Cytokines were present at much lower levels than growth factors, and the decline over time was less consistent. HM growth factors and cytokine levels vary between populations for unknown reasons. Levels of HM mediators decline at different rates postpartum, and these findings suggest specific biological roles for HM growth factors and cytokines in early postnatal development.

Exposures influencing total IgA level in colostrum.

Immunoglobulin A (IgA) is a predominant immunoglobulin present in human breast milk and is known to play an important role in infant gut immunity maturation. Breast milk composition varies between populations, but the environmental and maternal factors responsible for these variations are still unclear. We examined the relationship between different exposures and levels of IgA in colostrum. The objective of this study was to examine whether exposures analysed influence levels of IgA in colostrum. The present study used 294 colostrum samples from the MecMilk International cohort, collected from women residing in London, Moscow and Verona. Samples were analysed in automated Abbott Architect Analyser. We found an inverse correlation between time postpartum and colostrum total IgA level (r=-0.49, P<0.001). Adjusting for maternal parity, smoking, fresh fruit and fish consumption and allergen sensitization, multiple regression model showed that IgA levels were influenced by colostrum collection time (P<0.0001) and country of collection (P<0.01). Mode of delivery influence did not appear to be significant in univariate comparisons, once adjusted for the above maternal characteristics it showed a significant influence on total IgA (P=0.01). We conclude that the concentration of IgA in colostrum drops rapidly after birth and future studies should always consider this factor in analysis. IgA concentration varied significantly between countries, with the highest level detected in Moscow and lowest in Verona. Mode of delivery effect should be confirmed on larger cohorts. Further work is needed to determine ways to correct for IgA decline over time in colostrum, and to find the cause of variations in IgA levels between the countries.

Modulating breast milk composition - the key to allergy prevention?.

longed exclusive breastfeeding can prevent allergic disease [8, 9] . There are over 250 proteins in human breast milk including a wide variety of cytokines, inflammatory mediators, signalling molecules and soluble receptors [10] , yet there is limited literature on the relationship between maternal diet, breast milk immune constituents and allergy development. In this issue of International Archives of Allergy and Immunology , Kuitunen et al. [11] have investigated a potential role for IgA antibodies in breast milk as a mechanism through which probiotics prevent eczema. The study is well designed to answer this question, undertaken as part of a large probiotic/prebiotic intervention trial, on both colostrum and mature breast milk samples using appropriate methodology. The focus on IgA antibodies is justified by the established role of IgA of breast milk origin in gut mucosal immunity [12] . Kuitunen et al. [11] found no difference in total IgA concentration between treatment groups in contrast to others who found either increased [2] or decreased [3] IgA levels in breast milk from mothers treated with probiotics. Their findings with respect to food-specific IgA antibodies were mixed – for example high ovalbumin IgA in colostrum was associated with atopy by age 2 years – but low levels in mature breast milk were associated with eczema. Previous studies found probiotics alter levels of TGF1 or Allergic diseases such as asthma, eczema, hay fever and food allergy are the most common chronic diseases of childhood in many countries, and there is evidence that early life microbial exposure may be important in their development. The use of probiotic bacteria for preventing allergic disease has been tested in several randomised controlled trials and appears to be effective in preventing eczema but not allergic sensitisation [1] . The translation of this finding into clinical practice is hampered by the heterogeneity of interventions used in the trials and our limited understanding of how probiotics might work in this context. There is evidence that probiotic administration to pregnant and lactating women alters breast milk immune composition [2–4] . Although the specific changes identified are not always correlated with clinical outcomes, maternal probiotic supplementation during pregnancy and lactation can prevent eczema, and modulation of breast milk composition is the most likely mechanism [5] . The possibility that interventions which modify maternal immunity can impact infant immune responses by changing breast milk composition is supported by associations between breast milk composition and allergic outcomes [6, 7] . Variations in breast milk immune composition (and in infant response to breast milk immune constituents) may also explain some of the conflicting results of studies evaluating whether proPublished online: May 30, 2012

SIgA, TGF-β1, IL-10, and TNFα in Colostrum Are Associated with Infant Group B Streptococcus Colonization

Background Group B Streptococcus (GBS) is a major cause of mortality and morbidity in infants and is associated with transmission from a colonized mother at birth and via infected breastmilk. Although maternal/infant colonization with GBS is common, the majority of infants exposed to GBS remain unaffected. The association between breastmilk immune factors and infant colonization and disease prevention has not been elucidated. Objectives We have investigated the association between SIgA and cytokines in breastmilk and infant GBS colonization and clearance. Methods Mother/infant GBS colonization was determined in a prospective cohort of 750 Gambian mother/infant pairs followed to day 89 of life. Anti-GBS secretory IgA bound to the surface of whole bacteria was assessed by flow cytometry and a panel of 12 cytokines quantified by mesoscale discovery in colostrum, breastmilk and serum. Results Compared with infants receiving low anti-GBS SIgA in colostrum, infants receiving high anti-GBS SIgA were at decreased risk of GBS colonization for serotypes III and V. Infants colonized at day 6 were twice as likely to receive colostrum with high TGF-β1, TNFα, IL10, and IL-6 compared to uncolonized infants. Infants receiving high colostral TGF-β1, TNFα, and IL-6 had two-fold enhanced GBS clearance between birth and day 89. Conclusion Our results suggest that the infant GBS colonization risk diminishes with increasing anti-GBS SIgA antibody in breastmilk and that key maternally derived cytokines might contribute to protection against infant colonization. These findings might be leveraged to develop interventions including maternal vaccination that may reduce infant GBS colonization.

Worldwide Variation in Human Milk Metabolome: Indicators of Breast Physiology and Maternal Lifestyle?

Human milk provides essential substrates for the optimal growth and development of a breastfed infant. Besides providing nutrients to the infant, human milk also contains metabolites which form an intricate system between maternal lifestyle, such as the mother’s diet and the gut microbiome, and infant outcomes. This study investigates the variation of these human milk metabolites from five different countries. Human milk samples (n = 109) were collected one month postpartum from Australia, Japan, the USA, Norway, and South Africa and were analyzed by nuclear magnetic resonance. The partial least squares discriminant analysis (PLS-DA) showed separation between either maternal countries of origin or ethnicities. Variation between countries in concentration of metabolites, such as 2-oxoglutarate, creatine, and glutamine, in human milk, between countries, could provide insights into problems, such as mastitis and/or impaired functions of the mammary glands. Several important markers of milk production, such as lactose, betaine, creatine, glutamate, and glutamine, showed good correlation between each metabolite. This work highlights the importance of milk metabolites with respect to maternal lifestyle and the environment, and also provides the framework for future breastfeeding and microbiome studies in a global context.